This invention relates to the prevention and treatment of ocular diseases and in particular ocular hypertension and glaucoma. Glaucoma is a leading cause of irreversible blindness worldwide. Loss of visual function is considered inevitable with progressive degeneration of the optic nerve.
The number of patients worldwide is expected to be increasing with aging population. It was estimated that there were 60.5 million glaucoma patients in 2010, increasing to 79.6 million by 2020 with 21.8 millions in China. A considerable proportion of patients with ocular hypertension and glaucoma fail to have optimal control of intraocular pressure. These patients often require surgical intervention which may end up with undesirable visual outcome. There is a need for a new class of medication for lowering as well as preventing intraocular pressure rise in susceptible individuals.
All current forms of glaucoma medical treatment are targeted at lowering the intraocular pressure. (Sit 2008; Singh, 2008) These include sympathetic nerve stimulants (nonselective stimulants such as epinephrine and alpha2 stimulants such as apraclonidine), sympathetic nerve blockers (beta blockers including timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol and alpha1 blockers such as bunazosin hydrochloride), parasympathetic nerve agonists (pilocarpine), carbonic anhydrase inhibitors (acetazolamide and dorzolamide), and prostaglandin analogue (isopropyl unoprostone, latanoprost, travoprost, bimatoprost). These drugs either decrease the production of aqueous humor or increase the outflow facility through the trabecular meshwork and/or the uveoscleral outflow channels.
While aging, the use of topical steroids, myopia and a family medical history of glaucoma have been recognized as risk factors, lowering the intraocular pressure (IOP) remains the most effective approach in preventing visual loss in the glaucoma continuum. Although the pathologic mechanism for the development of glaucoma is not fully understood, it has been suggested that mutations in the myocilin gene (Jacobson, 2011; Jia 2009; Yam, 2007b), which may lead to an accumulation of defective myocilin gene product, might be a factor in a small subset that accounts for 2-4% of all the glaucoma patients (Alward, 1998; Fingert, 1999). If the above mechanism is correct, chaperones that reduce myocilin accumulation may be useful for this small group of patients. In reality, as most patients with glaucoma do not have a defective myocilin gene, this approach will be rendered inapplicable.
Sodium phenylbutyrate, (more specifically, a salt of 4-phenylbuytrate with structure shown in FIG. 1A), is a medication that has been used clinically to treat urea cycle disorders, sickle cell anemia and β-thalassemia (Brusilow, 1996; Collins, 1995; Dover, 1994.
Sodium phenylbutyrate is a short-chain fatty acid (FIG. 1B) and its chaperone effect has previously been shown to stabilize myocilin folding and facilitate intracellular trafficking and therefore reduce abnormal protein accumulation in cells that would lead to cell stress and death. (Yam, 2007a) It is therefore possible that patients with mutated myocilin gene defect can get beneficial effect from receiving sodium phenylbutyrate treatment. Oral administration of sodium phenylbutyrate has been shown very recently to rescue glaucoma phenotypes in mice expressing Y437H mutant myocilin transgene with normalization of elevated intraocular pressure when compared to untreated transgene mice (Zode et al., Association for Research in Vision and Ophthalmology 2011 Annual Meeting Abstract). Nonetheless, one would predict that this compound would have no effect on animals or patients with normal myocilin gene. As hereinafter shown, the opposite is true.
By way of support for the present invention but not as prior act, we found that sodium phenylbutyrate is effective in preventing and treating the intraocular pressure rise in an animal model of steroid-induced glaucoma in normal rabbits. (FIGS. 2A and 2B and FIG. 3). Such an animal model is commonly used for glaucoma research.
Moreover, if sodium phenylbutyrate is using its chaperone effect in preventing and treating the intraocular pressure rise in rabbits, one might predict that other chaperones may also work to lower the intraocular pressure. To explore this hypothesis, trimethylamine N-oxide (TMAO) was tested out using the same steroid-induced glaucoma model in rabbits. TMAO is another well known small-molecule chaperone (Gong, 2009; Kolter, 2003; Perlmutter, 2002); a natural osmolyte capable of stabilizing protein folding and acting as a protein stabilizer to protect ligand binding and polymerization against pressure inhibition. It improves folding and assembly of different proteins. Surprisingly, we found that TMAO was not effective at all in reducing the intraocular pressure rise as shown in the case of sodium phenylbutyrate. Specifically FIG. 4 illustrates the negative effect of trimethylamine N-oxide (TMAO) on dexamethasone-induced intraocular pressure changes. Fourteen New Zealand albino rabbits (7-week-old male) were divided into 5 groups. The right eyes received topical dexamethasone four times a day followed by topical TMAO (2, 10, 50, 100 and 300 mM) four times a day whereas the left eyes received topical dexamethasone four times a day followed by balanced salt solution, a physiological saline that acted as a control, four times a day. Topical TMAO did not prevent or treat the dexamethasone-induced intraocular pressure rise for the entire study period of 18 days (FIG. 4). The intraocular pressure in both eyes showed no significant difference. This suggests that prevention and treatment of elevation of steroid-induced intraocular pressure by sodium phenylbutyrate may not be related to chemical chaperone activity. This finding is very surprising.
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